Circulation Research. 2004;94:960-966
Published online before print February 19, 2004, doi: 10.1161/01.RES.0000122392.33172.09
Published online before print February 19, 2004, doi: 10.1161/01.RES.0000122392.33172.09
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase ß Inhibition During Reperfusion in Intact Rat Hearts
From the Medical College of Wisconsin, Department of Pharmacology and Toxicology, Milwaukee, Wis.
Correspondence to Garrett J. Gross, PhD, Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail ggross{at}mcw.edu
Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the 
-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 µg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 µg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9±2.6, 40.3±2.3, 46.6±1.6, 42.2±1.8 versus 60.0±1.1%, respectively; P<0.001) and showed similar protection when administered 5 minutes before reperfusion (43.6±2.3, 40.2±2.6, 44.8±2.8, 39.4±0.8%, respectively; P<0.001). Wortmannin, LY294002, and rapamycin were found to inhibit OIC; however, they did not abrogate SB21-induced infarct size reduction. At 5 minutes of reperfusion, both MOR and BW increased P-GSKß at Ser9 in the ischemic zone compared with vehicle (181±20, 178±15 versus 75±17 DU, respectively; P<0.05), and this effect was abrogated by prior administration of wortmannin or rapamycin in MOR-treated rats. Furthermore, no differences were seen in phosphorylation of GSK
(Ser21 or Tyr279) or phosphorylation of GSKß (Tyr216). These data indicate that OIC occurs via the phosphorylation of GSKß at Ser9 during reperfusion.
Key Words: reperfusion • glycogen synthase kinase • phosphatidylinositol-3 kinase • target of rapamycin • opioids
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